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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein Xiangrong Chen , Yusuf I Ali , Charlotte E. L. Fisher , Raquel Arribas-Bosacoma , Mohan B. Rajasekaran , Gareth Williams , Sarah Walker , Jessica R. Booth , Jessica J R. Hudson , S. Mark Roe , Laurence H. Pearl , Simon E. Ward , Frances M G. Pearl , Antony W. Oliver Elife 10 DOI: 10.7554/eLife.65339 Diamond Proposal Number(s): [20145] Open Access Show Abstract ▼ Abstract: BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.	Mar 2021
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks Ammar A E Ali , Gyula Timinszky , Raquel Arribas-bosacoma , Marek Kozlowski , Paul O Hassa , Markus Hassler , Andreas G Ladurner , Laurence H Pearl , Antony W. Oliver Nature Structural & Molecular Biology 19 (7), 685 - 692 DOI: 10.1038/nsmb.2335 PMID: 22683995 Diamond Proposal Number(s): [6385] Show Abstract ▼ Abstract: Poly(ADP-ribose) polymerase 1 (PARP1) is a primary DNA damage sensor whose (ADP-ribose) polymerase activity is acutely regulated by interaction with DNA breaks. Upon activation at sites of DNA damage, PARP1 modifies itself and other proteins by covalent addition of long, branched polymers of ADP-ribose, which in turn recruit downstream DNA repair and chromatin remodeling factors. PARP1 recognizes DNA damage through its N-terminal DNA-binding domain (DBD), which consists of a tandem repeat of an unusual zinc-finger (ZnF) domain. We have determined the crystal structure of the human PARP1-DBD bound to a DNA break. Along with functional analysis of PARP1 recruitment to sites of DNA damage in vivo, the structure reveals a dimeric assembly whereby ZnF1 and ZnF2 domains from separate PARP1 molecules form a strand-break recognition module that helps activate PARP1 by facilitating its dimerization and consequent trans-automodification.	Jun 2012

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